Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells

Diabetes. 2016 Dec;65(12):3680-3690. doi: 10.2337/db16-0001. Epub 2016 Aug 25.


In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism
  • Down-Regulation / drug effects
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Flow Cytometry
  • Forkhead Box Protein O1 / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin / pharmacology*
  • Insulin Resistance / physiology
  • Mice
  • Mice, Knockout
  • RNA, Small Interfering
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Activation / drug effects


  • Cited2 protein, mouse
  • Forkhead Box Protein O1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • RNA, Small Interfering
  • Repressor Proteins
  • Trans-Activators